The primary mechanism by which chemical carcinogens induce the malignant transformation of mammalian cells is unknown (Mishra and di Mayorca, 1974 Biochim. Biophys, Acta 355:205-219; Heidelberger, 1975. Ann. Rev. Biochem. 44:79-121). Four major theories for carcinogen action have been suggested: (1) selection of pre-existing transformed cells; (2) activation of viral oncogenic information; (3) somatic mutation and (4) epigenetic reprogramming of cellular differentiation. Strong arguments have been presented against the selection theory (Sanders and Burford, 1967. Nature 213:1171-1173; Embleton and Heidelberger, 1972 Int. J. Cancer 9:8-18). The remaining three theories are supported by a large body of experimental data detailing predicted correlations between one or another theory and chemically induced transformation (cf. Weinstein et al., 1975. In Vitro II, 130-141). However there is to date in the literature no direct evidence which allows one to distinguish with certainty between the last three hypotheses. In this laboratory we are trying to obtain the kind of direct evidence that we feel is needed to determine the mechanism of action of chemical carcinogens. In one series of experiments we are measuring the frequency of reversion to normal by various transformed lines and obtaining evidence against the oncogene theory of carcinogenesis. In a second series of experiments we are quantitatively studying the induction of conditionally transformed cells. This data is providing positive evidence for the somatic mutation theory of chemical carcinogenesis.